A. Diagnosing and Treating Inflammatory Bowel Disease and Irritable Bowel Syndrome
Fulminant ulcerative colitis is a worsening of ulcerative colitis characterized by a high white blood cell count and severe abdominal pain. At present, patients with fulminant ulcerative colitis are treated with high doses of steroids. In phase III-studies treatment with anti-TNFα has been investigated. Both drugs are general inhibitors of inflammation. They are effective in about 50% of cases but have serious adverse effects. Even if successfully treated fulminant ulcerative colitis has a tendency of recurring.
In patients with fulminant ulcerative colitis not responding to medical treatment prompt surgical intervention is mandatory. Ulcerative colitis is always restricted to the large intestine (colon). As a last measure the colon is resected, and an external ileostoma constructed. After a recovery period of at least 6 months and sometimes further medical treatment of rectal stump inflammation either ileorectal anastomosis or reconstructive surgery with a pelvic pouch will be performed in most patients to restore intestinal continuity. Both procedures entail loose stools about six times daily and disturbances in water- and mineral balances. There may also be fulminant episodes in Crohn's disease (fulminant Crohn's colitis), which are also serious conditions necessitating immediate medical and/or surgical intervention.
While the inflammation can be located in any part of the gastrointestinal tract in patients with Crohn's disease, it is usually confined to the most distal part of the small intestine and the first part of the large intestine (ileocaecal region). Medical treatment cannot cure the disease although anti-inflammatory drugs such as steroids and aza-thioprine relieve symptoms. Surgery with resection of stenotic and fistulating bowel segments is indicated in about 50% of patients; half of them will have recurrences and need further surgery. A method which can specifically turn off the inflammation in IBD and prevent recurrent disease in the individual patient thus is highly warranted.
B. Treating Conditions Associated with Metabolic Syndrome
The International Diabetes Foundation (IDF) define metabolic syndrome as follows:
For a person to be defined as having the metabolic syndrome they must have: Central obesity (defined as waist circumference ≧94 cm for Europid men and ≧80 cm for Europid women, with ethnicity specific values for other groups) plus any two of the following four factors:                raised triglyceride (TG) level: ≧150 mg/dL (1.7 mmol/L), or specific treatment for this lipid abnormality        reduced high-density lipoprotein (HDL) cholesterol: <40 mg/dL (1.03 mmol/L*) in males and <50 mg/dL (1.29 mmol/L*) in females, or specific treatment for this lipid abnormality        raised blood pressure (BP): systolic BP≧130 or diastolic BP≧85 mm Hg, or treatment of previously diagnosed hypertension        raised fasting plasma glucose (FPG)≧100 mg/dL (5.6 mmol/L), or previously diagnosed type 2 diabetes        
If above 5.6 mmol/L or 100 mg/dL, oral glucose tolerance test (OGTT) is strongly recommended but is not necessary to define presence of the syndrome.
While the pathogenesis of the metabolic syndrome and each of its components is complex and not well understood, central obesity and insulin resistance are acknowledged as important causative factors.
Adiposis dolorosa, or Dercum's disease, is a rare progressive condition characterized by multiple, painful, subcutaneous lipomas that usually occur in obese, postmenopausal women (Dercum FX. Three cases of a hitherto unclassified affection resembling in its grosser aspects obesity, but associated with special symptoms: adiposis dolorosa. Am J Med Sci 1892; 104:521-35, incorporated herein by reference in its entirety).
C. Treating Inflammatory Arthritis
Inflammatory arthritis describes a range of conditions, including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and gout, characterised by severe damage to joints throughout the body. Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis affecting about 1% of the total world population.
RA, similar to other forms of inflammatory arthritis is characterised by “synovitis” or inflammation of the synovial membrane, which lines the cavity of synovial joints. As the disease progresses, ongoing inflammation can lead to erosion and destruction of the joint causing significant pain, swelling and potentially deformity.
In many cases, the precise etiology of inflammatory arthritis is not well understood. However, all of these disorders fall within the category of “autoimmune conditions”, wherein disease pathogenesis is attributable in large part, to immune system dysregulation. RA in particular, is characterised by the presence of autoantibodies to “rheumatoid factor” and to “citrullinated peptides”. Moreover, the presence of inflammatory mediators, for example cytokines, is known to play a key role in fuelling disease progression. In this regard, TNFα has been identified as a central mediator of inflammation in RA, and therapies that block the activity of this molecule are being used successfully to alleviate the symptoms of this disease.
D. Treating Cancer
Cancer is a disease characterised by uncontrolled cell growth caused by accumulation of genetic mutations in the cellular DNA. There are over 200 types of different cancer classified according to the cell of origin from which the cancer or tumour first developed. Furthermore, cancers can be classified broadly as either solid tumours, for example breast cancer, colorectal cancer and melanoma, or as haematological malignancies such as leukaemias and lymphomas.
Solid tumours typically initiate and grow as an abnormal mass at a local site. However, during the course of cancer progression, the cells may acquire the ability to invade the underlying tissue and thereby enter the circulatory and/or lymphatic systems. These invasive properties ultimately allow solid tumours to metastasise to distal sites within the body, and it is metastasis combined with growth at secondary sites that accounts for the vast majority of cancer deaths.
In contrast to solid tumours, cancers such as leukaemias and lymphomas derive from cells of haematological origin, and therefore manifest as systemic diseases. In particular, chronic lymphocytic leukaemia, the most common form of leukaemia, develops from malignant lymphocytes originating in the bone marrow.
The body has many intrinsic mechanisms intended to guard against cancer development. In this regard, the immune system is thought to play a key role in eradicating cells harbouring genetic mutations. It follows therefore, that cancer cells often persist by evolving ways to avoid recognition by the cells of the immune system. In particular, it has been shown that elevated levels of T regulatory cells, both within the peripheral circulation and within the tumour microenvironment, underlie the immune suppression seen in cancer patients. The presence of increased numbers of regulatory T cells has also been identified as a barrier to the successful implementation of cancer immunotherapies.
E. Treating Mental Disorders
Schizophrenia is a mental disorder characterized by disintegration of thought processes and of emotional responsiveness. It most commonly manifests as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social or occupational dysfunction. The onset of symptoms typically occurs in young adulthood, with a global lifetime prevalence of about 0.3-0.7%. Diagnosis is typically based on observed behaviour and the patient's reported experiences.
Current treatments include antipsychotic medication, which primarily suppresses dopamine, and sometimes serotonin, receptor activity. Psychotherapy and vocational and social rehabilitation may also be important in treatment.
F. Treating Conditions Associated with Allergy
Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur to normally harmless environmental substances known as allergens; these reactions are acquired, predictable, and rapid. Allergy is a type I (or immediate) hypersensitivity and may be characterized by excessive activation of certain white blood cells, resulting in an extreme inflammatory response. Common allergic reactions include eczema, hives, hay fever, asthma attacks, food allergies, and reactions to the venom of stinging insects such as wasps and bees.
Mild allergies, such as hay fever, are highly prevalent in the human population. Allergies can play a major role in a range of conditions such as asthma.
A variety of tests now exist to diagnose allergic conditions; these include testing the skin for responses to known allergens or analyzing the blood for the presence and levels of allergen-specific IgE. Treatments for allergies include allergen avoidance, use of anti-histamines, steroids or other oral medications, immunotherapy to desensitize the response to allergen, and targeted therapy.
Allergic inflammation is an important pathophysiological feature of several medical conditions including allergic asthma, atopic dermatitis, allergic rhinitis and several ocular allergic diseases. Allergic reactions may generally be divided into two components; the early phase reaction, and the late phase reaction. While the contribution to the development of symptoms from each of the phases varies greatly between diseases, both are usually present and provide a framework for understanding allergic disease.
The early phase of the allergic reaction typically occurs within minutes following allergen exposure and may be referred to as the immediate allergic reaction or as a Type I allergic reaction. The reaction is caused by the release of histamine and mast cell granule proteins by a process called degranulation, as well as the production of leukotrienes, prostaglandins and cytokines, by mast cells following the cross-linking of allergen specific IgE molecules bound to mast cell FcεRI receptors. These mediators affect nerve cells causing itching, smooth muscle cells causing contraction (leading to the airway narrowing seen in allergic asthma), goblet cells causing mucus production, and endothelial cells causing vasodilatation and edema.
The products of the early phase reaction include chemokines and molecules that act on endothelial cells and cause them to express intercellular adhesion molecules (such as vascular cell adhesion molecule and selectins), which together result in the recruitment and activation of leukocytes from the blood into the site of the allergic reaction. Typically, the infiltrating cells observed in allergic reactions contain a high proportion of lymphocytes, and especially, of eosinophils. The recruited eosinophils will degranulate releasing a number of cytotoxic molecules (including Major Basic Protein and eosinophil peroxidase) as well as produce a number of cytokines such as IL-5. The recruited T-cells are typically of the Th2 variety and the cytokines they produce lead to further recruitment of mast cells and eosinophils as well as plasma cell isotype switching to IgE. The IgE binds to the mast cell FcεRI receptors and primes the individual for further allergic responses.
G. Treating Inflammatory Skin Diseases
Inflammatory skin disease defines a broad category of disorders characterised by mild to severe irritation and inflammation of the skin. These disorders can affect people of all ages, and include conditions such as acne, eczema or dermatitis, Rosacea and psoriasis. In most cases, there is no cure and patients with such conditions receive treatments to manage their symptoms.
Psoriasis and atopic dermatitis represent two of the commonest chronic inflammatory disorders of the skin, although, in both cases, the precise etiology of these diseases remains unknown. Psoriasis is characterised clinically by keratinocyte hyperproliferation and increased migration of inflammatory cells into the skin leading to epithelial hyperplasia and an excessive inflammatory response at the site of psoriatic plaques or lesions. Atopic dermatitis typically develops as an allergic reaction following exposure to irritants and/or environmental allergens and is associated with a dysregulated immune response occurring at the affected site.
In all inflammatory disorders of the skin, including psoriasis and atopic dermatitis, crosstalk between epidermal keratinocytes and cells of the immune system appears to play a central role in the pathogenesis of disease. For example, dendritic cells and effector T cells have been identified as key players in the development of psoriasis, and cytokines produced by these cells are known to stimulate keratinocyte proliferation and increase migration of inflammatory cells in the skin. In atopic dermatitis, cytokines released by immune cells trigger the inflammatory activation of keratinocytes.
H. Treating Multiple Sclerosis
Multiple sclerosis is a neurodegenerative disease affecting the central nervous system (CNS). Disease onset usually occurs in young adults between the ages of 20 and 40, however, the precise underlying cause of MS is unknown. There is currently no cure for this disabling disease and treatment is primarily focussed on management of symptoms.
Irrespective of disease etiology, the immune system has been found to play a central role in the pathogenesis of MS. In particular, the lesions that develop in the brain and/or spinal cord during disease progression are frequently characterised by an excessive inflammatory infiltrate and the presence of autoreactive CD4+/CD8+ T cells and autoreactive B cells. Furthermore, ongoing assault of the CNS mediated by a variety of inflammatory and/or immune cell types appears to be the primary cause of the nerve damage and in particular, the axon demyelination, associated with this disease.
I. Treating Cardiovascular Disease
Heart or cardiovascular diseases are the class of diseases that involve the heart or blood vessels. Thus disease may relate to the arteries and/or veins.
Obesity and diabetes mellitus are often linked to cardiovascular disease. C-reactive protein (CRP) is a common inflammatory marker that has been found to be present in increased levels in patients at risk for cardiovascular disease. Also osteoprotegerin, which is involved with regulation of a key inflammatory transcription factor called NF-κB has been found to be a risk factor of cardiovascular disease and mortality.
Atherosclerosis is a condition in which fatty material collects along the walls of arteries. This fatty material thickens, hardens to form a plaque, and may eventually block the arteries resulting in myocardial infarction. Atherosclerosis is a type of arteriosclerosis (which refers to any stiffening of the arteries).
Pieces of plaque can break off and move through the affected artery to smaller blood vessels, blocking them and causing tissue damage or death (embolization). This is a common cause of heart attack and stroke. Blood clots can also form around a tear (fissure) in the plaque leading to blocked blood flow. If the clot moves into an artery in the heart, lungs, or brain, it can cause a stroke, heart attack, or pulmonary embolism. In some cases, the atherosclerotic plaque is associated with a weakening of the wall of an artery leading to an aneurysm.
J. Treating Primary Sclerosing Cholangitis
Primary sclerosing cholangitis (PSC) is a chronic liver disease characterised by excessive inflammation and fibrosis of intra- and extra-hepatic bile ducts. Although the precise etiology of this disease remains unclear, PSC is considered to be an ‘autoimmune condition’ associated with immune system dysfunction. In particular, inflammation of the bile ducts plays a key role in disease progression. This excessive inflammation ultimately causes bile duct damage, which severely impairs the flow of bile from the liver to the duodenum resulting in a condition referred to as cholestasis. As the disease progresses, patients ultimately develop liver cancer or suffer from liver failure.
PSC is associated with an increased incidence of other forms of cancer, in particular cholangiosarcoma, cancer of the biliary tree, and colorectal cancer. The majority of patients with PSC also suffer with inflammatory bowel disease, in particular the form of this disease known as ulcerative colitis.
Many drugs have been found to be ineffective at halting PSC disease progression and treatment options are currently focussed around management of the complications associated with cholestasis. The only essentially curative treatment is liver transplantation.
K. Treating Respiratory Conditions
Respiratory tract disorders such as asthma and chronic obstructive pulmonary disease (COPD) are typically characterised by breathing difficulties as a result of reduced airflow to the lungs. These symptoms are often caused by inflammation of the airways; for example, chronic bronchitis is a form of COPD associated with excessive inflammation of the bronchi.
In addition to breathing difficulties, airway obstruction and associated inflammation can cause progressive lung damage. In the case of patients with COPD, permanent narrowing of the airways can lead to complications such as chest infections, heart failure and ultimately pulmonary failure.
COPD is a very common respiratory disease and in the majority of cases, smoking is the cause.
Patients are typically treated using inhalers containing “bronchodilator” drugs. However, these are of limited use for patients with permanently-constricted airways and/or end-stage disease characterised by extensive damage to the lungs.
L. Treating Conditions Associated with Sepsis
Sepsis is a severe clinical condition wherein the body undergoes a systemic inflammatory response to a known or suspected infection. Sepsis causes serious illness which can lead to multiple organ failure and death.
Sepsis is typically triggered as a result of the body's aberrant physiologic response to a blood-borne infection. In particular, a cascade of immunological activity involving rapid activation of neutrophils and macrophages, up-regulation of lymphocyte co-stimulatory molecules and rapid lymphocyte apoptosis, contributes significantly to the pathogenesis of this condition. The systemic release of cytokines, such as TNF-α, also causes dysregulation of the coagulation system and associated collapse of blood vessels. At the same time, disseminated activation of immunological pathways, such as the complement cascade, leads to wide-spread tissue and organ damage. A specific example of end-organ dysfunction is acute respiratory distress syndrome (ARDS). ARDS is characterized by inflammation of the lung parenchyma leading to impaired gas exchange with concomitant systemic release of inflammatory mediators causing inflammation, hypoxemia and frequently resulting in multiple organ failure.
The incidence of sepsis continues to increase worldwide, yet the mortality rate for this condition remains relatively high at between 20-40%. Improved knowledge of this complex condition is facilitating the development of new strategies for treatment; however, improved treatment options are still in high demand.
M. Apheresis
Apheresis is a treatment used for depletion of blood components, such as antibodies, low-density lipoproteins (LDL) and blood cells. Leukapheresis is the apheresis treatment used for removal of white blood cells, leukocytes. The patient is connected to an extracorporeal blood circulating system; the blood is drawn from a vein in one arm, passed through a column device and returned into the other arm of the patient. WO2010/029317 describes apheresis columns useful for treating inflammatory conditions including a chemokine immobilised on a solid support.